Sepsis is the major cause of morbidity and mortality in immunocompromised patients due to neutropenia following chemotherapy or radiotherapy. Recent advances in cancer management such as bone marrow transplantation, and the use of intensive chemotherapy and radiation therapy have added substantially to the number of patients that have survived cancer but due to the seriously impaired host defense system have lost their ability to resist or contain infections. Beside antibiotic therapy, an orchestrated response of the immune defense system towards bacteria is imperative in controlling and rapidly eliminating the offending pathogen.
Mast cells are functionally versatile and anatomically ubiquitous elements of the immune system capable of phagocytosing gram negative bacteria such as Klebsiella pneumoniae and E. coli. Recent studies using mast cell-deficient mice have provided unprecedented experimental evidence that mast cells play a pivotal role in host innate immune defense against gram negative bacterial infections by killing gram negative bacteria and recruiting neutrophils to the sites of active infection through the release of TNF.alpha. (Malaviya, R., et al., 1996, Nature, 381 (6577):77-80 and Echtenacher, et al., 1996, Nature, 381 (6577):75-7). Since mast cells are strategically located at the host environment interface, mast cells should be the first cell type to encounter invading pathogen. Augmenting bactericidal activity of mast cells would improve bacterial clearance and may rescue neutropenic patients from fatal consequences of gram negative bacterial infections.
Like effector cells of the innate immune system, mast cells are able to discern a variety of infectious agents that attach to them. It has been previously shown that mast cells could bind and phagocytose gram negative bacteria such as E. coli, K. pneumoniae, E. cloaece, and S. typhimurium. (Malaviya, R., et al., 1994, J. Immunol., 152 (4):1907-14 and Sher, A., et al., 1979, Lab Invest., 41(6):490-9). The mechanism of mast cell bactericidal activity involves generation of superoxide anion (Malaviya, R., et al., 1994, J. Immunol., 152 (4):1907-14). The killing of Shistosoma mansoni by mast cells have been shown to be mediated by the mast cell granule associated enzymes chymase or rat mast cell protease II (Sher, A., 1976, Nature, 263 (5575):334-6 and Sher, A., et al., 1983, J. Immunol., 131(3):1460-5).
In a systematic search to identify a potentiator of mast cell bactericidal activity, we identified 4-(3'bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline, WHI-P154 as a lead compound. WHI-P154 increased phagocytosis and killing of E. coli in vitro and bacterial clearance in vivo. WHI-P154 and structurally similar active hydroxy-halo-quinazoline derivatives provide a novel approach to combat infections by augmenting bactericidal activity of mast cells, which has applications in clinical settings.